CYTOTEC (MISOPROSTOL) ADMINISTRATION TO WOMEN WHO ARE PREGNANT
CAN CAUSE ABORTION, PREMATURE BIRTH, OR BIRTH DEFECTS. UTERINE RUPTURE HAS BEEN
REPORTED WHEN CYTOTEC WAS ADMINISTERED IN PREGNANT WOMEN TO INDUCE LABOR OR TO
INDUCE ABORTION BEYOND THE EIGHTH WEEK OF PREGNANCY (see also PRECAUTIONS and LABOR AND DELIVERY). CYTOTEC SHOULD NOT BE
TAKEN BY PREGNANT WOMEN TO REDUCE THE RISK OF ULCERS INDUCED BY NONSTEROIDAL
ANTI-INFLAMMATORY DRUGS (NSAIDs) (see CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS).

PATIENTS MUST BE ADVISED OF THE ABORTIFACIENT PROPERTY AND WARNED NOT TO GIVE
THE DRUG TO OTHERS.

Cytotec should not be used for reducing the risk of NSAID-induced ulcers in
women of childbearing potential unless the patient is at high risk of
complications from gastric ulcers associated with use of the NSAID, or is at
high risk of developing gastric ulceration. In such patients, Cytotec may be
prescribed if the patient

has had a negative serum pregnancy test within 2 weeks prior to beginning
therapy.

is capable of complying with effective contraceptive measures.

has received both oral and written warnings of the hazards of misoprostol,
the risk of possible contraception failure, and the danger to other women of
childbearing potential should the drug be taken by mistake.

will begin Cytotec only on the second or third day of the next normal
menstrual period.

Misoprostol is extensively absorbed, and undergoes rapid
de-esterification to its free acid, which is responsible for its clinical
activity and, unlike the parent compound, is detectable in plasma. The alpha
side chain undergoes beta oxidation and the beta side chain undergoes omega
oxidation followed by reduction of the ketone to give prostaglandin F
analogs.

In normal volunteers, Cytotec (misoprostol) is rapidly absorbed after oral
administration with a Tmax of misoprostol acid of 12 ± 3
minutes and a terminal half-life of 20–40 minutes.

There is high variability of plasma levels of misoprostol acid between and
within studies but mean values after single doses show a linear relationship
with dose over the range of 200–400 mcg. No accumulation of misoprostol acid was
noted in multiple dose studies; plasma steady state was achieved within two
days.

Maximum plasma concentrations of misoprostol acid are diminished when the
dose is taken with food and total availability of misoprostol acid is reduced by
use of concomitant antacid. Clinical trials were conducted with concomitant
antacid, however, so this effect does not appear to be clinically important.

After oral administration of radiolabeled misoprostol, about 80% of detected
radioactivity appears in urine. Pharmacokinetic studies in patients with varying
degrees of renal impairment showed an approximate doubling of T1/2, Cmax, and AUC compared to normals,
but no clear correlation between the degree of impairment and AUC. In subjects
over 64 years of age, the AUC for misoprostol acid is increased. No routine
dosage adjustment is recommended in older patients or patients with renal
impairment, but dosage may need to be reduced if the usual dose is not
tolerated.

Drug interaction studies between misoprostol and several nonsteroidal
anti-inflammatory drugs showed no effect on the kinetics of ibuprofen or
diclofenac, and a 20% decrease in aspirin AUC, not thought to be clinically
significant.

Pharmacokinetic studies also showed a lack of drug interaction with
antipyrine and propranolol when these drugs were given with misoprostol.
Misoprostol given for 1 week had no effect on the steady state pharmacokinetics
of diazepam when the two drugs were administered 2 hours apart.

The serum protein binding of misoprostol acid is less than 90% and is
concentration-independent in the therapeutic range.

After a single oral dose of misoprostol to nursing mothers, misoprostol acid
was excreted in breast milk. The maximum concentration of misoprostol acid in
expressed breast milk was achieved within 1 hour after dosing and was 7.6 pg/ml
(CV 37%) and 20.9 pg/ml (CV 62%) after single 200 µg and 600 µg misoprostol
administration, respectively. The misoprostol acid concentrations in breast milk
declined to less than 1 pg/ml at 5 hours post-dose.

Pharmacodynamics

Misoprostol has both antisecretory (inhibiting gastric acid
secretion) and (in animals) mucosal protective properties. NSAIDs inhibit
prostaglandin synthesis, and a deficiency of prostaglandins within the gastric
mucosa may lead to diminishing bicarbonate and mucus secretion and may
contribute to the mucosal damage caused by these agents. Misoprostol can
increase bicarbonate and mucus production, but in man this has been shown at
doses 200 mcg and above that are also antisecretory. It is therefore not
possible to tell whether the ability of misoprostol to reduce the risk of
gastric ulcer is the result of its antisecretory effect, its mucosal protective
effect, or both.

In vitro studies on canine parietal cells using
tritiated misoprostol acid as the ligand have led to the identification and
characterization of specific prostaglandin receptors. Receptor binding is
saturable, reversible, and stereospecific. The sites have a high affinity for
misoprostol, for its acid metabolite, and for other E type prostaglandins, but
not for F or I prostaglandins and other unrelated compounds, such as histamine
or cimetidine. Receptor-site affinity for misoprostol correlates well with an
indirect index of antisecretory activity. It is likely that these specific
receptors allow misoprostol taken with food to be effective topically, despite
the lower serum concentrations attained.

Misoprostol produces a moderate decrease in pepsin concentration during basal
conditions, but not during histamine stimulation. It has no significant effect
on fasting or postprandial gastrin nor on intrinsic factor output.

Effects on gastric acid secretion

Misoprostol, over the range of 50–200 mcg, inhibits basal and
nocturnal gastric acid secretion, and acid secretion in response to a variety of
stimuli, including meals, histamine, pentagastrin, and coffee. Activity is
apparent 30 minutes after oral administration and persists for at least 3 hours.
In general, the effects of 50 mcg were modest and shorter lived, and only the
200-mcg dose had substantial effects on nocturnal secretion or on histamine and
meal-stimulated secretion.

Uterine effects

Cytotec has been shown to produce uterine contractions that may
endanger pregnancy. (See boxed WARNINGS.)

In a series of small short-term (about 1 week) placebo-controlled
studies in healthy human volunteers, doses of misoprostol were evaluated for
their ability to reduce the risk of NSAID-induced mucosal injury. Studies of 200
mcg q.i.d. of misoprostol with tolmetin and naproxen, and of 100 and 200 mcg
q.i.d. with ibuprofen, all showed reduction of the rate of significant
endoscopic injury from about 70–75% on placebo to 10–30% on misoprostol. Doses
of 25–200 mcg q.i.d. reduced aspirin-induced mucosal injury and bleeding.

Two 12-week, randomized, double-blind trials in osteoarthritic
patients who had gastrointestinal symptoms but no ulcer on endoscopy while
taking an NSAID compared the ability of 200 mcg of Cytotec, 100 mcg of Cytotec,
and placebo to reduce the risk of gastric ulcer (GU) formation. Patients were
approximately equally divided between ibuprofen, piroxicam, and naproxen, and
continued this treatment throughout the 12 weeks. The 200-mcg dose caused a
marked, statistically significant reduction in gastric ulcers in both studies.
The lower dose was somewhat less effective, with a significant result in only
one of the studies.

Reduction of Risk of Gastric Ulcers Induced by Ibuprofen, Piroxicam, or Naproxen [No. of patients with ulcer(s) (%)]

* Statistically significantly different from placebo at the 5% level.†Combined data from Study No. 1 and Study No. 2.

In these trials there were no significant differences between Cytotec and
placebo in relief of day or night abdominal pain. No effect of Cytotec in
reducing the risk of duodenal ulcers was demonstrated, but relatively few
duodenal lesions were seen.

In another clinical trial, 239 patients receiving aspirin 650–1300 mg q.i.d.
for rheumatoid arthritis who had endoscopic evidence of duodenal and/or gastric
inflammation were randomized to misoprostol 200 mcg q.i.d. or placebo for 8
weeks while continuing to receive aspirin. The study evaluated the possible
interference of Cytotec on the efficacy of aspirin in these patients with
rheumatoid arthritis by analyzing joint tenderness, joint swelling, physician's
clinical assessment, patient's assessment, change in ARA classification, change
in handgrip strength, change in duration of morning stiffness, patient's
assessment of pain at rest, movement, interference with daily activity, and ESR.
Cytotec did not interfere with the efficacy of aspirin in these patients with
rheumatoid arthritis.

Cytotec (misoprostol) is indicated for reducing the risk of NSAID (nonsteroidal
anti-inflammatory drugs, including aspirin)–induced gastric ulcers in patients
at high risk of complications from gastric ulcer, e.g., the elderly and patients
with concomitant debilitating disease, as well as patients at high risk of
developing gastric ulceration, such as patients with a history of ulcer. Cytotec
has not been shown to reduce the risk of duodenal ulcers in patients taking
NSAIDs. Cytotec should be taken for the duration of NSAID therapy. Cytotec has
been shown to reduce the risk of gastric ulcers in controlled studies of 3
months' duration. It had no effect, compared to placebo, on gastrointestinal
pain or discomfort associated with NSAID use.

Caution should be employed when administering Cytotec
(misoprostol) to patients with pre-existing cardiovascular disease.

Information for patients

Women of childbearing potential using Cytotec to decrease the
risk of NSAID-induced ulcers should be told that they must not be pregnant when
Cytotec therapy is initiated, and that they must use an effective contraception
method while taking Cytotec.

Cytotec is intended for administration along with nonsteroidal
anti-inflammatory drugs (NSAIDs), including aspirin, to decrease the chance of
developing an NSAID-induced gastric ulcer.

Cytotec should be taken only according to the directions given by a
physician.

If the patient has questions about or problems with Cytotec, the physician
should be contacted promptly.

THE PATIENT SHOULD NOT GIVE CYTOTEC TO ANYONE ELSE.
Cytotec has been prescribed for the patient's specific condition, may not be the
correct treatment for another person, and may be dangerous to the other person
if she were to become pregnant.

The Cytotec package the patient receives from the pharmacist will include a
leaflet containing patient information. The patient should read the leaflet
before taking Cytotec and each time the prescription is renewed because the
leaflet may have been revised.

Keep Cytotec out of the reach of children.

SPECIAL NOTE FOR WOMEN: Cytotec may cause abortion
(sometimes incomplete), premature labor, or birth defects if given to pregnant
women.

Cytotec is available only as a unit-of-use package that includes a leaflet
containing patient information. See Patient Information at the end of this
labeling.

Drug interactions

See Clinical
Pharmacology. Cytotec has not been shown to interfere with the
beneficial effects of aspirin on signs and symptoms of rheumatoid arthritis.
Cytotec does not exert clinically significant effects on the absorption, blood
levels, and antiplatelet effects of therapeutic doses of aspirin. Cytotec has no
clinically significant effect on the kinetics of diclofenac or ibuprofen.

Animal toxicology

A reversible increase in the number of normal surface gastric
epithelial cells occurred in the dog, rat, and mouse. No such increase has been
observed in humans administered Cytotec for up to 1 year.

An apparent response of the female mouse to Cytotec in long-term studies at
100 to 1000 times the human dose was hyperostosis, mainly of the medulla of
sternebrae. Hyperostosis did not occur in long-term studies in the dog and rat
and has not been seen in humans treated with Cytotec.

Carcinogenesis, mutagenesis, impairment of
fertility

There was no evidence of an effect of Cytotec on tumor occurrence
or incidence in rats receiving daily doses up to 150 times the human dose for 24
months. Similarly, there was no effect of Cytotec on tumor occurrence or
incidence in mice receiving daily doses up to 1000 times the human dose for 21
months. The mutagenic potential of Cytotec was tested in several in vitro assays, all of which were negative.

Misoprostol, when administered to breeding male and female rats at doses 6.25
times to 625 times the maximum recommended human therapeutic dose, produced
dose-related pre- and post-implantation losses and a significant decrease in the
number of live pups born at the highest dose. These findings suggest the
possibility of a general adverse effect on fertility in males and females.

Pregnancy: Pregnancy Category XTeratogenic effects

See boxed WARNINGS. Congenital anomalies sometimes
associated with fetal death have been reported subsequent to the unsuccessful
use of misoprostol as an abortifacient, but the drug's teratogenic mechanism has
not been demonstrated. Several reports in the literature associate the use of
misoprostol during the first trimester of pregnancy with skull defects, cranial
nerve palsies, facial malformations, and limb defects.

Cytotec is not fetotoxic or teratogenic in rats and rabbits at doses 625 and
63 times the human dose, respectively.

Nonteratogenic effects

See boxed WARNINGS. Cytotec may endanger pregnancy (may
cause abortion) and thereby cause harm to the fetus when administered to a
pregnant woman. Cytotec may produce uterine contractions, uterine bleeding, and
expulsion of the products of conception. Abortions caused by Cytotec may be
incomplete. If a woman is or becomes pregnant while taking this drug to reduce
the risk of NSAID-induced ulcers, the drug should be discontinued and the
patient apprised of the potential hazard to the fetus.

Labor and delivery

Cytotec can induce or augment uterine contractions. Vaginal
administration of Cytotec, outside of its approved indication, has been used as
a cervical ripening agent, for the induction of labor and for treatment of
serious postpartum hemorrhage in the presence of uterine atony. A major adverse
effect of the obstetrical use of Cytotec is the hyperstimulation of the uterus
which may progress to uterine tetany with marked impairment of uteroplacental
blood flow, uterine rupture (requiring surgical repair, hysterectomy, and/or
salpingo-oophorectomy), or amniotic fluid embolism. Pelvic pain, retained
placenta, severe genital bleeding, shock, fetal bradycardia, and fetal and
maternal death have been reported.

There may be an increased risk of uterine tachysystole, uterine rupture,
meconium passage, meconium staining of amniotic fluid, and Cesarean delivery due
to uterine hyperstimulation with the use of higher doses of Cytotec, including
the manufactured 100 mcg tablet. The risk of uterine rupture increases with
advancing gestational ages and with prior uterine surgery, including Cesarean
delivery. Grand multiparity also appears to be a risk factor for uterine
rupture.

The effect of Cytotec on later growth, development, and functional maturation
of the child when Cytotec is used for cervical ripening or induction of labor
has not been established. Information on Cytotec's effect on the need for
forceps delivery or other intervention is unknown.

Nursing mothers

Misoprostol is rapidly metabolized in the mother to misoprostol
acid, which is biologically active and is excreted in breast milk. There are no
published reports of adverse effects of misoprostol in breast-feeding infants of
mothers taking misoprostol. Caution should be exercised when misoprostol is
administered to a nursing woman.

Pediatric use

Safety and effectiveness of Cytotec in pediatric patients have
not been established.

The following have been reported as adverse events in subjects
receiving Cytotec:

Gastrointestinal

In subjects receiving Cytotec 400 or 800 mcg daily in clinical
trials, the most frequent gastrointestinal adverse events were diarrhea and
abdominal pain. The incidence of diarrhea at 800 mcg in controlled trials in
patients on NSAIDs ranged from 14–40% and in all studies (over 5,000 patients)
averaged 13%. Abdominal pain occurred in 13–20% of patients in NSAID trials and
about 7% in all studies, but there was no consistent difference from
placebo.

Diarrhea was dose related and usually developed early in the course of
therapy (after 13 days), usually was self-limiting (often resolving after 8
days), but sometimes required discontinuation of Cytotec (2% of the patients).
Rare instances of profound diarrhea leading to severe dehydration have been
reported. Patients with an underlying condition such as inflammatory bowel
disease, or those in whom dehydration, were it to occur, would be dangerous,
should be monitored carefully if Cytotec is prescribed. The incidence of
diarrhea can be minimized by administering after meals and at bedtime, and by
avoiding coadministration of Cytotec with magnesium-containing antacids.

Gynecological

Women who received Cytotec during clinical trials reported the
following gynecological disorders: spotting (0.7%), cramps (0.6%),
hypermenorrhea (0.5%), menstrual disorder (0.3%) and dysmenorrhea (0.1%).
Postmenopausal vaginal bleeding may be related to Cytotec administration. If it
occurs, diagnostic workup should be undertaken to rule out gynecological
pathology. (See boxed WARNINGS.)

Elderly

There were no significant differences in the safety profile of
Cytotec in approximately 500 ulcer patients who were 65 years of age or older
compared with younger patients.

Additional adverse events which were reported are categorized as
follows:

Incidence greater than 1%

In clinical trials, the following adverse reactions were reported
by more than 1% of the subjects receiving Cytotec and may be causally related to
the drug: nausea (3.2%), flatulence (2.9%), headache (2.4%), dyspepsia (2.0%),
vomiting (1.3%), and constipation (1.1%). However, there were no significant
differences between the incidences of these events for Cytotec and
placebo.

Causal relationship unknown

The following adverse events were infrequently reported. Causal
relationships between Cytotec and these events have not been established but
cannot be excluded:

The toxic dose of Cytotec in humans has not been determined.
Cumulative total daily doses of 1600 mcg have been tolerated, with only symptoms
of gastrointestinal discomfort being reported. In animals, the acute toxic
effects are diarrhea, gastrointestinal lesions, focal cardiac necrosis, hepatic
necrosis, renal tubular necrosis, testicular atrophy, respiratory difficulties,
and depression of the central nervous system. Clinical signs that may indicate
an overdose are sedation, tremor, convulsions, dyspnea, abdominal pain,
diarrhea, fever, palpitations, hypotension, or bradycardia. Symptoms should be
treated with supportive therapy.

It is not known if misoprostol acid is dialyzable. However, because
misoprostol is metabolized like a fatty acid, it is unlikely that dialysis would
be appropriate treatment for overdosage.

The recommended adult oral dose of Cytotec for reducing the risk
of NSAID-induced gastric ulcers is 200 mcg four times daily with food. If this
dose cannot be tolerated, a dose of 100 mcg can be used. (See Clinical Pharmacology:
Clinical studies.) Cytotec should be taken for the duration of NSAID
therapy as prescribed by the physician. Cytotec should be taken with a meal, and
the last dose of the day should be at bedtime.

Renal impairment

Adjustment of the dosing schedule in renally impaired patients is
not routinely needed, but dosage can be reduced if the 200-mcg dose is not
tolerated. (See Clinical
Pharmacology.)

Read this leaflet before taking Cytotec®
(misoprostol) and each time your prescription is renewed, because the leaflet
may be changed.

Cytotec (misoprostol) is being prescribed by your doctor to decrease the
chance of getting stomach ulcers related to the arthritis/pain medication that
you take.

Do not take Cytotec to reduce the risk of NSAID-induced ulcers if you are
pregnant. (See boxed WARNINGS.) Cytotec can cause abortion
(sometimes incomplete which could lead to dangerous bleeding and require
hospitalization and surgery), premature birth, or birth defects. It is also
important to avoid pregnancy while taking this medication and for at least one
month or through one menstrual cycle after you stop taking it. Cytotec has been
reported to cause the uterus to rupture (tear) when given after the eighth week
of pregnancy. Rupture (tearing) of the uterus can result in severe bleeding,
hysterectomy, and/or maternal or fetal death.

If you become pregnant during Cytotec therapy, stop taking Cytotec and
contact your physician immediately. Remember that even if you are on a means of
birth control it is still possible to become pregnant. Should this occur, stop
taking Cytotec and contact your physician immediately.

Cytotec may cause diarrhea, abdominal cramping, and/or nausea in some people.
In most cases these problems develop during the first few weeks of therapy and
stop after about a week. You can minimize possible diarrhea by making sure you
take Cytotec with food.

Because these side effects are usually mild to moderate and usually go away
in a matter of days, most patients can continue to take Cytotec. If you have
prolonged difficulty (more than 8 days), or if you have severe diarrhea,
cramping and/or nausea, call your doctor.

Take Cytotec only according to the directions given by your physician.

Do not give Cytotec to anyone else. It has been prescribed for your specific
condition, may not be the correct treatment for another person, and would be
dangerous if the other person were pregnant.

This information sheet does not cover all possible side effects of Cytotec.
This patient information leaflet does not address the side effects of your
arthritis/pain medication. See your doctor if you have questions.

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